Roles of Ca(2+)/calmodulin-dependent protein kinase II in subcellular expression of striatal N-methyl-D-aspartate receptors in l-3, 4-dihydroxyphenylalanine-induced dyskinetic rats.

Background: The role of N-Methyl-D-aspartate (NMDA) receptors is critical to the development of l-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) in Parkinson's disease (PD). Ca2+/calmodulin-dependent protein kinase II (CaMKII) is thought to regulate the expression and activation of NMDA receptors in LID, but the interaction between LID and CaMKIImodulated NMDA receptor activity is not clear so far. Methods: We used 6-hydroxydopamine-lesioned rats to create PD rat model, and at least 21 days of L-dopa was administrated followed with or without microinjection of CaMKII inhibitor KN-93 into the lesioned striatum of all the PD rats and sham rats. A surface receptor cross-linking assay was used to distinguish expression of striatal NMDA receptors in surface and intracellular compartments. Results: l-dopa treatment enhanced surface levels of GluN1 expression and reduced its intracellular expression, but did not change total levels of GluN1 protein in the lesioned striatum. In contrast, l-dopa decreased GluN2A surface expression but increased its intracellular expression. l-dopa increased GluN2B expression preferentially in the surface compartment. We also found that l-dopa increased CaMKII autophosphorylation at T286 in striatal neurons. The inhibition of CaMKII by microinjecting CaMKII inhibitor KN-93 into the lesioned striatum largely reversed the l-dopa-induced changes in three subunits. In addition, dyskinetic behaviors of animals were observed alleviated after treatment of KN-93. Conclusion: Our research indicates that long-term L-dopa administration activates CaMKII in striatal neurons. Activated CaMKII is involved at least in part in mediating L-dopa-induced changes of NMDA receptors surface/intracellular expression.